While glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are highly effective at lowering HbA1c, currently available GLP-1 RA delivery options are suboptimal; SC administrations hinder patient adherence and oral administrations have lower bioavailability due to enzymatic instability and insufficient gastrointestinal absorption. A novel approach to deliver GLP-1 RAs with superior bioavailability and better patient adherence would further improve the antidiabetes efficacy of GLP-1 RAs. Hence, this study assesses an oral formulation facilitating intestinal absorption of DD02S, a new GLP-1RA. Biological activities, gastrointestinal stabilities and Caco-2 permeability study of DD02S were performed in vitro. The in vivo efficacy of the oral formulation was evaluated by intraduodenal injection in rats. DD02S was formulated as enteric coated tablets and orally administered in dogs. Pharmacological efficacy was demonstrated by repeated dosing in db/db mice. DD02S was designed to introduce a ligand and fatty acid to facilitate cellular uptake via intestinal transporters, increase enzyme stability, and enable reversible plasma protein binding without loss of potency. The oral formulation enhanced the intestinal stability as well as permeation via trans and paracellular routes. The increased intestinal absorption was confirmed by intraduodenal injection in rats. Following the oral administration of the enteric coated tablets to dogs, the mean bioavailability ranged from 5.0-10.1% with variability of 78-117% and pharmacokinetic parameters were suitable for once daily oral dosing. In the antidiabetes efficacy study of DD02S, significant reduction of HbA1c was observed in a dose-dependent manner. This study demonstrates the potential antidiabetes efficacy of DD02S with once daily oral dosing. Our novel approach for oral delivery is promising to development of other oral peptide therapeutics.


E.Park: Employee; D&D Pharmatech. O.Jeon: Employee; D&D Pharmatech. J.Park: Employee; D&D Pharmatech. J.Choi: Employee; D&D Pharmatech. J.Shin: Employee; D&D Pharmatech. S.Lim: Board Member; D&D pharmatech. S.Park: Board Member; D&D Pharmatech. S.Lee: Board Member; D&D Pharmatech.

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